Showing papers on "HER2/neu published in 1998"

Recombinant Humanized anti-HER2 Antibody (Herceptin) Enhances the Antitumor Activity of Paclitaxel and Doxorubicin Against HER2/neu Overexpressing Human Breast Cancer Xenografts

Abstract: Recombinant humanized anti-HER2 antibody, rhuMAb HER2, inhibits the growth of breast cancer cells overexpressing HER2 and has clinical activity. We explored in preclinical models its capacity to enhance the tumoricidal effects of paclitaxel and doxorubicin. In cultures of naturally HER2-overexpressing cancer cells, rhuMAb HER2 inhibited growth and enhanced the cytotoxic effects of paclitaxel. Treatment of well established BT-474 breast cancer xenografts overexpressing HER2 in athymic mice with rhuMAb HER2 resulted in a dose-dependent antitumor activity. In combination studies, treatment with paclitaxel and rhuMAb HER2 or doxorubicin and rhuMAb HER2 resulted in greater inhibition of growth than that observed with any agent alone. The combination of paclitaxel and rhuMAb HER2 resulted in the highest tumor growth inhibition and had a significantly superior complete tumor regression rate when compared with either paclitaxel or rhuMAb HER2 alone. Clinical trials that are built on these results are under way.

Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment.

Abstract: PURPOSETo determine the toxicity, pharmacokinetics, response rate, and response duration of intravenous (i.v.) administration of recombinant, humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) plus cisplatin (CDDP) in a phase II, open-label, multicenter clinical trial for patients with HER2/neu-overexpressing metastatic breast cancer.PATIENTS AND METHODSThe study population consisted of extensively pretreated advanced breast cancer patients with HER2/neu overexpression and disease progression during standard chemotherapy. Patients received a loading dose of rhuMAb HER2 (250 mg i.v.) on day 0, followed by weekly doses of 100 mg i.v. for 9 weeks. Patients received CDDP (75 mg/m2) on days 1, 29, and 57.RESULTSOf 37 patients assessable for response, nine (24.3%) achieved a PR, nine (24.3%) had a minor response or stable disease, and disease progression occurred in 19 (51.3%). The median response duration was 5.3 months (range, 1.6-18). Grade III or IV toxicity was observed in 22 of 39 patients (56%). T...

Identification of HER2/neu-derived peptide epitopes recognized by gastric cancer-specific cytotoxic T lymphocytes.

Abstract: We have derived HLA-A2.1-restricted, gastric cancer-specific cytotoxic T lymphocyte (CTL) lines by repetitive in vitro stimulation of tumor-associated lymphocytes (TAL) with autologous tumor cells. The HER2/neu specificity of these gastric cancer-specific CTLs was demonstrated using HER2/neu-transfected cell lines and HER2/neu-expressing tumors, and with a set of HER2/neu-derived peptide epitopes. Gastric cancer-specific CTLs specifically lysed autologous and allogeneic HLA-A2.1+, HER2/neu+ gastric cancer cells, HER2/neu-transfected C1R/A2 cell lines (HLA-A2.1+, HER2+) and HLA-A2.1-transfected SW626 tumor cell lines (HLA-A2.1+, HER2+). This recognition could be inhibited by anti-HLA-A2 antibody or by cold target HER2/neu-transfected C1R/A2 cells. Our results demonstrate that the HER2/neu-encoded HLA-A2.1-associated epitopes recognized by CTLs are presented as naturally processed peptides on gastric cancer lines. Furthermore, 3 of 19 tested HER2/neu-derived peptide epitopes [HER2(9106), HER2(9369), HER2(9689)], which all bound HLA-A2.1 with high (IC50 < 50 nM) affinity, were able to sensitize HLA-A2+ C1R/A2 cells to be recognized by the gastric cancer-specific CTLs, demonstrating the immunodominance of these epitopes. In conclusion, our findings implicate HER2/neu-derived epitopes as potential candidates for novel immunotherapy and vaccine strategies against gastric cancer. Int. J. Cancer 78:202–208, 1998. © 1998 Wiley-Liss, Inc.

The PEA3 Ets transcription factor is a downstream target of the HER2/Neu receptor tyrosine kinase.

Abstract: The HER2/neu gene, which is overexpressed in 20-30% of human breast tumors, encodes a receptor tyrosine kinase that functions through multiple signaling pathways to regulate the activity of nuclear transcription factors. We have reported that PEA3, an Ets family transcription factor, is overexpressed in HER2/Neu-induced breast tumors and their metastases. To account for the increased levels of PEA3 in these tumors we have suggested that HER2/Neu enhances PEA3 transcriptional activity, which then acts to stimulate expression of the PEA3 gene. This hypothesis is consistent with the occurrence of PEA3 binding sites in the PEA3 promoter and with the ability of PEA3 to transactivate this promoter. To learn whether HER2/Neu indeed regulates PEA3 activity we measured the capacity of constitutively-activated HER2/Neu to affect PEA3-dependent reporter gene expression. Coexpression of PEA3 and HER2/Neu stimulated PEA3-dependent reporter gene expression to a much greater extent than did either protein alone suggesting that HER2/Neu upregulates the transcriptional activity of PEA3. To define the pathway whereby HER2/Neu functions we employed dominant-negative mutants of signaling proteins known to be downstream of HER2/Neu. Overexpression of Rap1a, a Ras-related protein capable of antagonizing Ras function, completely inhibited the ability of HER2/Neu to stimulate PEA3-dependent gene expression. Ras is known to stimulate at least two mitogen-activated protein kinase (MAPK) cascades, the extracellular-regulated kinase (ERK) cascade and the stress-activated kinase (SAPK) or Jun kinase (JNK) cascade. Similarly, HER2/Neu activated both ERKs and SAPKs/JNKs in a Ras-dependent fashion. Dominant-inhibitory mutants in either the ERK or SAPK/JNK cascades partially inhibited HER2/Neu activation of PEA3-dependent gene expression. These findings suggest that HER2/Neu regulates PEA3 activity through two different Ras-dependent MAPK pathways.

Overexpression of the oncogene c-erbB-2 (HER2/neu) and response to chemotherapy in patients with ovarian cancer.

Abstract: This study was designed to determine whether c-erbB-2 overexpression could be used as a marker to identify a subgroup of patients with ovarian cancer more likely than others to benefit from chemotherapy. Paraffin sections from tissue blocks from 208 patients with newly diagnosed untreated ovarian cancer were analyzed for c-erbB-2 overexpression. All patients underwent postoperative platin-based chemotherapy. Patients with c-erbB-2 positive tumors had a significantly worse prognosis as compared to patients with c-erbB-2 negative tumors (p = 0.0003). c-erbB-2 findings were not related to tumor stage or histologic findings. There was clear evidence of a dose-response effect with regard to survival in patients with c-erbB-2 negative tumors, which could not be seen in patients with c-erbB-2 positive tumors (p = 0.0341 vs p = 0.3775). We conclude that there is a significant total dose-response effect of platin-based chemotherapy in ovarian cancer patients without overexpression of c-erbB-2 but not in patients with c-erbB-2 overexpression. Overexpression of c-erbB-2 may be a useful marker to identify patients who are most likely to benefit from high-dose chemotherapy.

Detection of p105 (c-erbB-2, HER2/neu) serum levels by a new ELISA in patients with ovarian carcinoma.

Abstract: Background: Immunohistochemical detection of the oncogene c-erbB-2 (HER2/neu) has been shown to be an important prognostic marker in ovarian cancer. In this study we evaluated a new developed polyclonal detector antibody-based ELISA for the extracellular domain of p185 to determine whether the soluble oncoprotein fragment p105 can be detected in the serum of ovarian cancer patients. Materials and methods: The relationship between p105 serum levels and various tumor parameters in 53 patients with newly diagnosed, untreated ovarian cancer was studied. Serum specimens were obtained prior initial surgery, and p105 levels were determined using a new developed, polyclonal detector antibody-based human neu quantitative ELISA assay. Results: Using the polyclonal detector antibody-based ELISA, elevated p105 serum levels were not related to tumor stage, grade, histology and residual tumor after primary surgery. Conclusions: These results suggest that particular statements concerning the preoperatively taken p105 level using the polyclonal antibody-based ELISA in patients with primary ovarian cancer cannot be brawn yet.

Radioimmunotherapy targeting of HER2/neu oncoprotein on ovarian tumor using lead-212-DOTA-AE1. J Nucl Med

Abstract: UNLABELLED The specificity, toxicity and efficacy of lead (212Pb) radioimmunotherapy were evaluated in nude mice bearing the SK-OV-3 human ovarian tumor cell line expressing the HER2/neu proto-oncogene. METHODS The therapeutic agent used was the tumor-specific anti-HER2/neu monoclonal antibody AE1 conjugated to 212Pb, 212Bi being the daughter and thus the source of the alpha-particle and beta emissions. A bifunctional derivative of tetraazacyclododecanetetraacetic acid (p-SCN-Bz-DOTA) was used to couple 212Pb to the anti-HER2/neu monoclonal antibody AE1. The chelating agent did not alter the binding affinity to its antigenic target or the pharmacokinetics and tissue distribution of the AE1 antibody. Toxicity and therapeutic efficacy of 212Pb-AE1 were evaluated in nude mouse ascites or solid tumor models, wherein SK-OV-3 cells were administered i.p. or s.c., respectively. RESULTS The dose-limiting acute toxicity after i.v. administration of 212Pb-AE1 was bone marrow suppression, which was observed at doses above 25 microCi. Therefore, doses of 10 and 20 microCi were used in efficacy trials. The i.p. administration of 212Pb-AE1 3 days after i.p. tumor inoculation led to a significant (P2 = 0.015) prolongation of tumor-free survival. In a second model, i.v. treatment with 212Pb-AE1 3 days after s.c. tumor inoculation prevented subsequent tumor development in all animals treated with 10 or 20 microCi of 212Pb-AE1 (P2 = 0.002 compared to control groups). This efficacy in the adjuvant setting was antibody specific because treatments with equivalently labeled control antibody or unlabeled AE1 antibody or no treatment were less effective. The rate of growth of small (mean tumor volume, 15 mm3) SK-OV-3 tumors was modestly inhibited. However, tumor growth was not inhibited in mice bearing larger (mean tumor volume, 146 mm3) SK-OV-3 tumors by the administration of a single dose of 10 or 20 microCi of 212Pb-AE1. CONCLUSION Lead-212-AE1 as an intact radiolabeled monoclonal antibody may be of only modest value in the therapy of bulky solid tumors due to the short physical half-life of 212Pb and time required to achieve a useful tumor-to-normal tissue ratio of radionuclide after administration. However, the radiolabeled monoclonal antibody may be useful in therapy of tumors in the adjuvant setting. Furthermore, 212Pb may be of value in select situations, including treatment of leukemia, intercavitary therapy or strategies that target vascular endothelial cells of tumors.

CHAPTER 4.7 – Targeting of sterically stabilized liposomes to cancers overexpressing HER2/neu proto-oncogene

Abstract: This chapter describes HER2 (c-erbB-2, neu) oncoprotein as a target recognition molecule in cancer. In contrast to a number of previous liposomal targeting systems for anticancer agents, sterically stabilized anti-HER2 immunoliposomes were not only capable of target-specific binding and internalization by cancer cells in culture but were also able to cross the vascular barrier. Malignant phenotype is often associated with the expression of proto-oncogene. The HER2 proto-oncogene encodes a 185 kDa receptor tyrosine kinase, which belongs to the family of receptor tyrosine kinases, including also the products of epidermal growth factor HER3 and HER4 genes. Overexpression of HER2 was first observed in 20–30% of breast carcinomas and was associated with aggressive tumor growth, high recurrence rate, and poor prognosis for the patients. Further studies showed ubiquitous overexpression of HER2 in a variety of malignancies, including cancers of the ovary, endometrium, lung, stomach, pancreas, bladder, and prostate. Over the past decade, the introduction and refinement of “long-circulating” liposomes preparation techniques, and “remote loading” methods for drug loading into liposomes greatly advanced liposomal pharmacology. The “rational design” of cancer cell-targeted sterically stabilized liposomes leads to a re-evaluation of tumor targeting paradigms and opens new avenues for better a treatment of cancer.